Abstract 2629: Epigenetic modulation of the MYC oncogene as a potential novel therapy for HCC
Authors: William Senapedis, Elmer Figueroa, Kayleigh Gallagher, Jeremiah Farelli, Robert Lyng, Charles O'Donnell, Joseph Newman, Thomas McCauley
Journal: Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC), the fourth leading cause of cancer deaths, represents an unmet medical need with few therapeutic options. Sorafenib has been used as a systemic therapy for HCC for &amp;gt;10 years but patients frequently develop resistance with oncogenic c-MYC (MYC) identified as a correlating prognostic factor. MYC over-expression is associated with aggressive disease in up to ~70% of HCC. While MYC represents an attractive therapeutic target, it has historically been considered undruggable, largely because it lacks a structured binding pocket and its expression is tightly autoregulated. The MYC gene and its regulatory elements are part of an insulated genomic domain (IGD), a chromatin looping region anchored by CTCF. Here we describe our approach to specifically modulate levels of MYC expression by utilizing targeted mRNA-encoded proteins, Omega Epigenomic Controllers (OECs), to mediate epigenetic regulation while potentially overcoming MYC autoregulation. For screening, putative OECs were directed to 2 loci on the MYC IGD. Identified target loci were used to design optimized OECs, including development candidate OTX-2002. We characterized OTX-2002 in HCC cell lines, measuring MYC mRNA and cell viability. OTX-2002 was tested for durable epigenetic and transcriptomic changes. Changes in MYC protein levels and pathway signaling were measured using proteomic methods. Finally, we analyzed activity of OTX-2002 in in vivo subcutaneous (subQ) and orthotopic HCC models by assessing tumor volume, tumor-associated bioluminescence (BLI) and immunohistochemistry (IHC). OTX-2002 was effective at decreasing MYC mRNA, protein and cell viability in HCC cells while sparing normal cells. In HCC cells, OTX-2002 median EC50 of inhibition is &amp;lt;0.001 ng/mL for MYC mRNA and 120 ng/mL for cell viability. Importantly, the effects of OTX-2002 persisted for &amp;gt;2 weeks, providing durable MYC mRNA repression. IV delivery of OTX-2002 in lipid nanoparticles at 3 and 6 mg/kg Q5D in a Hep 3B subQ model in athymic nude mice demonstrated statistically significant tumor growth inhibition (TGI) of 54% and 63%, respectively, by Day 23 compared to negative control. OTX-2002-treated mice did not have a significant decrease in bodyweight (BW) compared to negative control or sorafenib-treated mice. IHC of OTX-2002 and control treated tumors showed significant down-regulation of MYC with reduced proliferation (Ki67) and increased apoptosis (Caspase 3). In a Hep 3B orthotopic model 3 mg/kg OTX-2002 Q5D showed a comparable reduction of BLI to sorafenib at 50 mg/kg QD without the reduction in BW. Our findings identify a therapeutic in vitro and in vivo approach that enables transcriptional modulation of the MYC oncogene through precise epigenomic programming of the IGD in which it resides. Targeting MYC in this manner may represent a potentially differentiated and viable approach to the treatment of HCC in humans. Citation Format: William Senapedis, Elmer Figueroa, Kayleigh Gallagher, Jeremiah Farelli, Robert Lyng, Charles O'Donnell, Joseph Newman, Thomas McCauley. Epigenetic modulation of the MYC oncogene as a potential novel therapy for HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2629.